TY - JOUR AB - While βcatenin has been demonstrated as an essential molecule and therapeutic target for various cancer stem cells (CSCs) including those driven by MLL fusions, here we show that transcriptional memory from cells of origin predicts AML patient survival and allows βcateninindependent transformation in MLLCSCs derived from hematopoietic stem cell (HSC)enriched LSK population but not myeloid–granulocyte progenitors. Mechanistically, βcatenin regulates expression of downstream targets of a key transcriptional memory gene, Hoxa9 that is highly enriched in LSKderived MLLCSCs and helps sustain leukemic selfrenewal. Suppression of Hoxa9 sensitizes LSKderived MLLCSCs to βcatenin inhibition resulting in abolishment of CSC transcriptional program and transformation ability. In addition, further molecular and functional analyses identified Prmt1 as a key common downstream mediator for βcatenin/Hoxa9 functions in LSKderived MLLCSCs. Together, these findings not only uncover an unexpectedly important role of cells of origin transcriptional memory in regulating CSC selfrenewal, but also reveal a novel molecular network mediated by βcatenin/Hoxa9/Prmt1 in governing leukemic selfrenewal. AU - Lenhard,B AU - Siriboonpiputtana,T AU - So,CWE DO - 10.15252/embj.201797994 PY - 2017/// SN - 0261-4189 TI - Transcriptional memory of cells of origin overrides βcatenin requirement of MLL cancer stem cells T2 - EMBO Journal UR - http://dx.doi.org/10.15252/embj.201797994 ER -